Synthesis and QSAR studies on hypotensive 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines

A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are important for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT(2A) receptor binding affinities of these compounds suggests a possible role of 5-HT(2A) receptors in mediating the hypotensive action of title compounds.     

Nematicidal prenylated flavanones from Phyllanthus niruri

Two prenylated flavanones have been isolated from the hexane extract of Phyllanthus niruri plant. The structure of these flavanones were established as 8-(3-Methyl-but-2-enyl)-2-phenyl chroman-4-one (1) and 2-(4-hydroxyphenyl)-8-(3-methyl-but-2-enyl)-chroman-4-one (2) on the basis of spectral analysis. These were evaluated for nematicidal activity against root-knot, Meloidogyne incognita, and reniform, Rotylenchulus reniformis, nematodes. Compound 2 exhibited nematicidal activity at par with the standard carbofuran (LC50 3.3 and 3.1ppm, respectively) when tested against reniform nematode. The LC50 value against root-knot nematode was found to be 14.5ppm. Compound 1 however, showed moderate activity against both the test nematodes.     

Androgen receptor status predicts response to chemotherapy, not risk of breast cancer in Indian women

Voltage gated potassium channels have been extensively studied in relation to cancer. In this review, we will focus on the role of two potassium channels, Ether à-go-go (Eag), Human ether à-go-go related gene (HERG), in cancer and their potential therapeutic utility in the treatment of cancer. Eag and HERG are expressed in cancers of various organs and have been implicated in cell cycle progression and proliferation of cancer cells. Inhibition of these channels has been shown to reduce proliferation both in vitro and vivo studies identifying potassium channel modulators as putative inhibitors of tumour progression. Eag channels in view of their restricted expression in normal tissue may emerge as novel tumour biomarkers.     

Synthesis and in vitro study of 14-aryl-14H-dibenzo[a.j]xanthenes as cytotoxic agents

A simple and expedient method for the synthesis of a series of 14-aryl-14H-dibenzo[a.j]xanthenes is described through a one-pot condensation of β-naphthol with aryl aldehydes catalysed by TaCl₅ under solvent-free conventional heating. The major advantages of the present method are: high yields, less reaction time, solvent-free condition and easy purification of the products. The synthesized 14-aryl-14H-dibenzo[a.j]xanthenes were evaluated against a panel of six human cancer lines of different tissues. Synthesized compound 3o showed IC₅₀ of 37.9 and 41.3 μM against Colo-205 and 502713, respectively, whereas 3g showed IC₅₀ of 41.9 μM against Colo-205.     

Novel Techniques for Weak Alignment of Proteins in Solution Using Chemical Tags Coordinating Lanthanide Ions

A molecule with an anisotropic magnetic susceptibility is spontaneously aligned in a static magnetic field. Alignment of such a molecule yields residual dipolar couplings and pseudocontact shifts. Lanthanide ions have recently been successfully used to provide an anisotropic magnetic susceptibility in target molecules either by replacing a calcium ion with a lanthanide ion in calcium-binding proteins or by attaching an EDTA derivative to a cysteine residue via a disulfide bond. Here we describe a novel enantiomerically pure EDTA derived tag that aligns stronger due to its shorter linker and does not suffer from stereochemical diversity upon lanthanide complexation. We observed residual (15)N,(1)H-dipolar couplings of up to 8 Hz at 800 MHz induced by a single alignment tensor from this tag.     

Lead-induced oxidative stress and hematological alterations and their response to combined administration of calcium disodium EDTA with a thiol chelator in rats

The therapeutic efficacy of calcium disodium ethylenediaminetetracetic acid (CaNa(2)EDTA) and the two thiol chelators, 2,3-dimercaptopropane 1-sulfonate (DMPS) and monoisoamyl dimercaptosuccinic acid (MiADMSA) was studied, both individually and in combination, in reducing lead concentration in blood and soft tissues and in restoring lead induced altered biochemical variables in rats. Exposure to subacute dose of lead implicated a critical role of reactive oxygen species (ROS) and oxidative stress in altering the normal values of these variables. Exposure to lead caused a significant inhibition of blood delta-aminolevulinic acid dehydratase (ALAD), an important enzyme in the haem synthesis pathway and glutathione (GSH) level. These changes were also accompanied by inhibition of ALAD activity in kidney, delta-aminolevulinic acid synthase (ALAS) activities in liver and changes in platelet counts in whole blood suggesting disturbed haem synthesis pathway. Lead exposure also led to a pronounced depletion of brain GSH contents, superoxide dismutase (SOD) activity, an increase in thiobarbituric acid reactive substances (TBARS), and activity of glutathione S-transferase (GST). Specific activities of membrane-bound enzymes, acetylcholinesterase (AChE) and monoamine oxidase (MAO), were significantly inhibited on lead exposure. These biochemical changes were correlated with increased uptake of lead in blood and soft tissues. Post lead exposure treatment with MiADMSA in particular provided significant recovery in altered biochemical variables besides significant depletion of tissue lead burden. Treatment with CaNa(2)EDTA and DMPS individually had only moderate beneficial effects on tissue oxidative stress, although they were equally effective in the removal of tissue lead burden. Tissue zinc and copper levels did not depict any significant depletion, although changes like marked depletion of zinc following CaNa(2)EDTA and copper after MiADMSA administration were of some concern. Combined administration of CaNa(2)EDTA, particularly with MiADMSA, was the most effective treatment protocol compared to all other treatments. It can be concluded from our present results that combined therapy with CaNa(2)EDTA and MiADMSA proved significantly better in restoring biochemical and clinical variables over monotherapy with these chelating agents against subacute lead exposure in adult rats.     

Primary amino acid sequence of follicle-stimulating hormone from human pituitary glands. I. alpha subunit.

Follicle-stimulating hormone of a high state of physicochemical and biological purity was isolated from acetone-preserved human pituitary glands. The follicle-stimulating hormone was dissociated into alpha and beta subunits by treatment with 8 M urea and the subunits were separated by ion exchange chromatography on DEAE-Sephadex A-25. The subunits were freed of undissociated or reassociated follicle-stimulating hormone by gel filtration on Sephadex G-100. For the establishment of the primary amino acid sequence, the alpha subunit was reduced and either carboxyamidomethylated or S-aminoethylated prior to a thermolytic or a tryptic digestion. Each digest was gel filtered on a column of Sephadex G-50 to separate the glycopeptides from the peptides. The glycopeptides and the peptides were purified further by sequential gel filtration on Sephadex G-25, G-15, and Bio-Gel-P-2 and were isolated by high voltage electrophoresis at pH 6, 3.5, and 2. The purity of the isolated peptides was ascertained further by amino acid analysis. The amino acid sequences of the peptides were determined by Edman degradation followed by subtractive amino acid analysis. COOH-terminal sequences were established by digestion with carboxypeptidases A and B. The primary amino acid sequence of human follicle-stimulating hormone-alpha is identical to that of human chorionic gonadotropin-alpha and differs from that of human luteinizing hormone-alpha in having the tripeptide Ala-Pro-Asx- at the NH2-terminal end.     

Molecular cloning and characterization of Brugia malayi hexokinase

5' EST from filarial gene database has been subjected to 3' rapid amplification of cDNA ends (RACE), semi-nested PCR and PCR to obtain full-length cDNA of Brugia malayi. Full-length hexokinase gene was obtained from cDNA using gene specific primers. The elicited PCR product was cloned, sequenced and expressed as an active enzyme in Escherichia coli. Sequence analysis of B. malayi hexokinase (BmHk) revealed 59% identity with nematode Caenorhabditis elegans but low similarity with all other available hexokinases including human. BmHk, an apparent tetramer with subunit molecular mass of 72 kDa, was able to phosphorylate glucose, fructose, mannose, maltose and galactose. The Km values for glucose, fructose and ATP were found to be 0.035+/-0.005, 75+/-0.3 and 1.09+/-0.5 mM respectively. BmHk was strongly inhibited by ADP, glucosamine, N-acetyl glucosamine and mannoheptulose. The recombinant enzyme was found to be activated by glucose-6-phosphate. ADP exhibited noncompetitive inhibition with the substrate glucose (Ki=0.55 mM) while, mixed type of inhibition was observed with inorganic pyrophosphate (PPi) when ATP was used as substrate (Ki=9.92 microM). The enzyme activity is highly dependent on maintenance of free sulfhydryl groups. CD analysis indicated that BmHk is composed of 37% alpha-helices and 26% beta-sheets. The observed differences in kinetic properties of BmHk as compared to host enzyme may facilitate designing of specific inhibitors against BmHk.     

J-domain protein, Jac1p, of yeast mitochondria required for iron homeostasis and activity of Fe-S cluster proteins

J-proteins are molecular chaperones with a characteristic domain predicted to mediate interaction with Hsp70 proteins. We have previously isolated yeast mutants of the mitochondrial Hsp70, Ssq1p, in a genetic screen for mutants with altered iron homeostasis. Here we describe the isolation of mutants of the J-domain protein, Jac1p, using the same screen. Mutant jac1 alleles predicted to encode severely truncated proteins (lacking 70 or 152 amino acids) were associated with phenotypes strikingly similar to the phenotypes of ssq1 mutants. These phenotypes include activation of the high affinity cellular iron uptake system and iron accumulation in mitochondria. In contrast to iron accumulation, Fe-S proteins of mitochondria were specifically deficient. In jac1 mutants, like in ssq1 mutants, processing of the Yfh1p precursor protein from intermediate to mature forms was delayed. In the genetic backgrounds used in this study, jac1 null mutants were found to be viable, permitting analysis of genetic interactions. The Deltajac1 Deltassq1 double mutant was more severely compromised for growth than either single mutant, suggesting a synthetic or additive effect of these mutations. Overexpression of Jac1p partially suppressed ssq1 slow growth and vice versa. Similar mitochondrial localization and similar mutant phenotypes suggest that Ssq1p and Jac1p are functional partners in iron homeostasis.     

Internet: a major resource for toxicologists

Use of the Internet in developing countries is now growing faster. Internet has created a new conduit not only for communication but also in the access, sharing and exchange of information among scientists. The Internet is now viewed as the world's biggest library where retrieval of scientific literature and other information resources are possible within seconds. Large volumes of toxicological information resources are available on the Internet. This review outlines some sites that may be of great importance and useful to the toxicologist.